tbuckley/cabot-search huggingface dataset:
Abstract 6216: Pre-ribosomal RNA mediates HR repair via the BRCA1/BARD1 complex
Authors: Duo Wu, Huang Huang, Tenglong Chen, Xiaochen Gai, Song Liu, Hu He, Song Shi, Xiaochun Yu
Journal: Cancer Research (2023)

Abstract The BRCA1/BARD1 complex plays a key role in DNA double-stand break (DSB) repair in both somatic cells and germ cells. However, the underlying molecular mechanism by which this complex mediates DSB repair remains elusive. Here, we show that the recruitment of the BRCA1/BARD1 complex to the unsynapsed axis of the XY body in male germ cells is mediated by pre-rRNA. Similarly, the BRCA1/BARD1 complex associates with pre-rRNA in somatic cells, which targets the BRCA1/BARD1 complex to DSBs. The interactions between the BRCT domains of the BRCA1/BARD1 complex and pre-rRNA induces liquid-liquid phase separations, which may be the molecular basis of DSB-induced nuclear foci formation of the BRCA1/BARD1 complex. Pre-rRNA also mediates BRCA1-dependent homologous recombination (HR). Cancer-associated mutations in the BRCT domains of BRCA1 and BARD1 abolish the interaction with pre-rRNA. We developed novel RNA pol I inhibitors to suppress pre-rRNA biogenesis, which not only abolished HR repair but also sensitized tumor cells to PARP inhibitor treatment. Collectively, this study reveals that pre-rRNA is a functional partner of the BRCA1/BARD1 complex in the DSB repair. It is also a potential therapeutic target for cancer therapy. Citation Format: Duo Wu, Huang Huang, Tenglong Chen, Xiaochen Gai, Song Liu, Hu He, Song Shi, Xiaochun Yu. Pre-ribosomal RNA mediates HR repair via the BRCA1/BARD1 complex. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6216.
Abstract 2040: Molecular dynamic simulation of intermediates connecting KRAS and PRMT5 insight for targeting KRAS
Authors: Isaac V. Silverman, Yitzchak F. Stein, Michael Shawn Gerber, Radhashree Maitra, Sanjay Goel
Journal: Cancer Research (2023)

Abstract Introduction: Therapeutic approaches to target mutant KRAS is in progress, and transcription regulator PRMT5 (Protein arginine methyltransferase) has been previously reported to be a viable, surrogate target. Mutation of oncogenic KRAS is prevalent in several cancer types often rendering aggressiveness to the disease. Herein we used extensive molecular dynamics simulations to understand the intermediate complexities of the cross-talk. Methodology: GROMACS is a Molecular Dynamics Simulation software that renders a topology regulated by Newton’s Laws that can be employed to simulate interactions between proteins. Utilizing the STRING database, multiple pathways from KRAS linked to PRMT5 were extrapolated. Confidence values were determined. Protein complexes were downloaded from RCSB archives. Protein pairs were submitted to HDOCK for docking. Proteins were separated by chain identities, using PYMOL. Proteins were solvated and paired in GROMACS, and charges were neutralized. Each complex underwent energy minimization to configure the proteins in the most energetically favorable conformation. The complex was equilibrated and simulated. XmGrace was used to graph radius gyration between both proteins and their stabilities. The data produced were used to analyze the favorable interaction of the various pathways. Results: Three pathways were analyzed, with high, intermediate, and low confidence values of interaction. The intermediate mediators were simulated in pairs and energy scoring was performed for each interaction. The radius of gyration (Rg) values was calculated for each protein in its respective pathway. A cutoff of 10 nanoseconds was used to confirm stability. A scale was constructed to predict the order of operations of each pathway. HRAS was determined to be actively involved in the crosstalk. Conclusion: The crosstalk between PRMT5 and KRAS can be achieved through three different biochemical pathways with varying levels of confidence. Potentially, if one pathway is affected, an alternative route could be activated to achieve signaling toward PRMT5. These pathways introduce a more targeted approach toward discovering therapeutic advances against KRAS. More simulations are underway to compare the interactions of wildtype and mutant KRAS with their respective pathway intermediates. Citation Format: Isaac V. Silverman, Yitzchak F. Stein, Michael Shawn Gerber, Radhashree Maitra, Sanjay Goel. Molecular dynamic simulation of intermediates connecting KRAS and PRMT5 insight for targeting KRAS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2040.
Abstract 14: The impact of genetic background on cancer phenotypes of mouse models
Authors: Dale A. Begley, Debra M. Krupke, Steven B. Neuhauser, Emily L. Jocoy, John P. Sundberg, Carol J. Bult
Journal: Cancer Research (2023)

Abstract The laboratory mouse is the premier animal model system for in vivo studies of the genetic and genomic basis of cancer in humans. Although thousands of mouse models have been generated, finding relevant data and knowledge about these models is complicated by a general lack of compliance in the published literature with nomenclature and annotation standards for genes, alleles, mouse strains, and cancer types. The Mouse Models of Human Cancer database (MMHCdb; tumor.informatics.jax.org) is an expertly curated knowledgebase of cancer phenotypes reported for diverse types of mouse models of human cancer such as inbred mouse strains, genetically engineered mouse models (GEMMs), Patient Derived Xenografts (PDXs), and mouse genetic diversity panels (e.g., the Collaborative Cross). MMHCdb includes data on more than 60,000 mouse models for over 1200 tumor classifications curated from more than 25,000 peer-reviewed publications. One of the primary goals of the MMHCdb is to highlight the impact of genetic background on the incidence and presentation of different tumor types in mice. The same allele on different backgrounds can result in very different cancer characteristics and, therefore, impact the appropriateness of a model for a specific research application. In MMHCdb, users can review the impact of genetic background on the frequency of spontaneous tumors for inbred mouse strains using an interactive table generated from different published and unpublished data sources. In addition, color-coded tabular summaries of individual papers are available that allow researchers to quickly assess how genetic background affects cancer phenotypes in the mouse models reported in a specific publication. We will highlight examples of how genetic background can profoundly change the types and frequencies of tumor types that can be expected in mouse models of human cancer. MMHCdb is supported by NCI R01 CA089713 Citation Format: Dale A. Begley, Debra M. Krupke, Steven B. Neuhauser, Emily L. Jocoy, John P. Sundberg, Carol J. Bult. The impact of genetic background on cancer phenotypes of mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 14.
Abstract 6201: Identification of SP-002, a highly selective USP1 inhibitor effectively inhibits HRD tumor growth and displays low hematotoxicity risk
Authors: Feng Zhou, Zhengtao Li, Lei Zhou, Wei Zhu, Jiyan Zhang, Wenqing Yang, Liting Xue, Xiaokang Qin, Ping Chen, Renhong Tang
Journal: Cancer Research (2023)

Abstract Tumors with homologous repair deficiencies (HRD) are sensitive to agents interrupting DNA repair. The deubiquitinase USP1 involves in the DNA damage response by translesion synthesis and Fanconi anemia pathway. And the synthetic lethality of USP1 and HRD is well reported. Moreover, deficiency of USP1 or its downstream pathway leads to hypersensitivity of HRD tumors to PARP inhibition. In addition, target-related hematotoxicity is widely observed in serval DNA Damage Response (DDR) pathway inhibitors, including PARP and ATR inhibitors, which limits the combination therapy. Here, we reported SP-002, a highly selective USP1 inhibitor, displayed monotherapy potential and combination activity with PARP inhibitor in HRD cancers. In the biochemical assay, SP-002 strongly inhibited USP1 enzyme with IC50 of 15.7 nM, and potently inhibited proliferation of BRCA1-mutant MDA-MB-436 breast cell (GI50, 47.4 nM). SP-002 demonstrated synergistic anti-proliferation effects in combination of olaparib, a PARP inhibitor, in MDA-MB-436 cells. And further results revealed that the combination significantly enhances the DNA damage burden and cells apoptosis. Moreover, synergistic activities of SP-002 and olaparib also were observed in a panel of HRD cell lines, such as UWB1.289, Capan-1, MDA-MB-453 and NCI-H292. In a human hematopoietic stem cells based in vitro hematotoxicity assay, SP-002 showed no significant inhibition on lineage-specific (myeloid, erythroid, and megakaryocytic) cell differentiation and survival. In comparison, positive controls, 5-fluorouracil and olaparib significantly attenuated those primary cells both on differentiation and survival, which was consistent with the hematological toxicity observed in human. Oral administration of SP-002 led to completely tumor growth inhibition in MDA-MB-436 xenograft model, and combination of SP-002 and olaparib resulted in tumor regression. In conclusion, SP-002, a selective and potent USP1 inhibitor without significant hematotoxicity, that demonstrated excellent efficacy on treatment of HRD cancers. Citation Format: Feng Zhou, Zhengtao Li, Lei Zhou, Wei Zhu, Jiyan Zhang, Wenqing Yang, Liting Xue, Xiaokang Qin, Ping Chen, Renhong Tang. Identification of SP-002, a highly selective USP1 inhibitor effectively inhibits HRD tumor growth and displays low hematotoxicity risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6201.
Abstract 2054: Whole-genome sequencing based homologous recombination deficiency testing for precision oncology of breast cancers
Authors: Ryul Kim, Seongyeol Park, Joonoh Lim, Boram Yi, Jaemo Koo, Sangmoon Lee, Jeong Seok Lee, Yeon Hee Park, Young Seok Ju
Journal: Cancer Research (2023)

Abstract Breast cancers (BCs) with defects in homologous recombination repair (HRR) pathway depend on the Poly (ADP-ribose) polymerase enzymes (PARP) for their survival and thus are sensitive to PARP inhibitors (PARPi). To screen out BCs with homologous recombination deficiency (HRD), germline mutations in BRCA genes have been tested, which constitute approximately 5% of unselected BC patients. However, a substantial proportion of BCs show HRD phenotypes despite the absence of BRCA inactivating mutations in germline. Herein, we apply whole-genome sequencing (WGS) and whole-transcriptome sequencing (WTS) in 332 samples from 325 BC patients for characterizing their HRD phenotypes for PARPi treatments. Of 325 BC patients, 75 cases (23.1%) showed remarkable HRD phenotypes, based on mutational signatures of HRR abrogation. Intriguingly, 51 cases do not harbor any germline mutations in HR-related genes including BRCA1 and BRCA2. The whole-genome portrait of these samples was similar to that of HRD-positive BCs with germline mutation in HRR pathway, but showed markedly distinctive features from HRD-negative BCs. With a notable exception of BRCA1, the second most common somatic mutation in HRD-positive BCs without germline mutation, the mutational landscape of the whole study samples was primarily determined by hormone receptor and HER2 positivity, not by HRD status. Likewise, WTS-based clusters determined in an unsupervised manner were highly dependent on the histological subtype of BC, not on HRD status or germline mutations in the HRR pathway. Notably, differentially expressed gene and gene set enrichment analysis revealed that HRD-positive BCs had an increased inflammatory activity compared to BCs with proficient HR. Overall, our analysis demonstrate that WGS enables better classification of the HR status in BC than conventional BRCA germline testing, suggesting WGS as a rapid and sensitive tool for screening breast cancers for PARPi treatment. Citation Format: Ryul Kim, Seongyeol Park, Joonoh Lim, Boram Yi, Jaemo Koo, Sangmoon Lee, Jeong Seok Lee, Yeon Hee Park, Young Seok Ju. Whole-genome sequencing based homologous recombination deficiency testing for precision oncology of breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2054.
Abstract 1968: A multiomic spatial atlas of breast cancer in women of African ancestry
Authors: Jasmine T. Plummer, Nadezhda Nikulina, Ayodele Omotoso, Destiny Burnett, Priscilla Coelho, Simone Badal, Judith Hurley, Carmen Gomez, Ha Yeun Ji, Maycon Marcao, Felipe Dezem Segato, Oliver Braubach, Sophia George
Journal: Cancer Research (2023)

Abstract The US Black population consists of both US-born Black and immigrant Black populations from the Caribbean and Africa. Normal tissues in Black individuals, independent of their country of birth or residence, are woefully understudied. Yet, Black individuals disproportionately develop aggressive pathologic diseases and are treatment refractory or resistant, thus leaing to premature deaths. In women, breast cancer is more common among US Black women, and the most common non-viral driven cancer in African and Caribbean countries. Furthermore, Black women develop this disease younger than other ancestral groups and have a higher incidence aggressive pathologies, such as metaplastic and triple-negative breast cancer. With the African-Caribbean Cancer Consortium (AC3) and Transatlantic Gynecologic Cancer Research Consortium, we have created a multiomic spatial atlas of triple-negative and other breast cancers across Africa, the Caribbean, and among US-Black individuals. We performed ultrahigh-plex RNA and protein spatial phenotyping on the PhenoCycler-Fusion (PCF). The PCF is a fast end-to-end spatial biology platform that enables whole-slide spatial readouts of RNA and protein moieties at single-cell resolution. Multiomic spatial phenotyping of tissues allowed for the detection of novel cell populations associated with a given African ancestry linking unique immune/stromal cell types to the outcome and severity of breast cancer. Here, we aim to develop a benchmark that confidently measures and interprets ancestral genomic differences at the cellular level. Deciphering the relationship between African ancestry, aggressive disease biology, and early onset will enable the characterization of the tissue composition and the proportion of cell sub-populations implicated in tumorigenesis and the interplay with germline genetics. Citation Format: Jasmine T. Plummer, Nadezhda Nikulina, Ayodele Omotoso, Destiny Burnett, Priscilla Coelho, Simone Badal, Judith Hurley, Carmen Gomez, Ha Yeun Ji, Maycon Marcao, Felipe Dezem Segato, Oliver Braubach, Sophia George. A multiomic spatial atlas of breast cancer in women of African ancestry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1968.
Abstract 4999: Preclinical evaluation of MCLA-129, a bispecific antibody targeting EGFR and c-MET on solid tumor cells, in comparison with amivantamab
Authors: David J.J. de Gorter, Alexandre Deshiere, Arjen Kramer, Martijn van Rosmalen, Franziska Mortensen, Cecile Geuijen
Journal: Cancer Research (2023)

Abstract The HGF/c-MET pathway is frequently upregulated in tumors that are resistant to EGFR tyrosine kinase inhibitors. MCLA-129 is an antibody-dependent cellular cytotoxicity (ADCC) enhanced Biclonics® that targets epidermal growth factor receptor (EGFR) and c-MET in non-small cell lung cancer (NSCLC) and other solid tumors. MCLA-129 is a potent inhibitor of tumor growth applying various mechanisms of action (MOA), including inhibition of c-MET and EGFR signaling, antibody-dependent cellular phagocytosis (ADCP) and ADCC. Here we compared the MOA of MCLA-129 with the MOA of the EGFR-c-MET bispecific antibody amivantamab. The binding of MCLA-129 to tumor cells expressing different levels of EGFR and c-MET was quantified using radiolabeled antibodies. Scatchard plot analysis showed that the affinity of MCLA-129 for both c-MET and EGFR is in the low nanomolar range. In FACS, MCLA-129 and amivantamab show similar binding to tumor cells harboring EGFR or c-MET exon14-skipping mutations. Crossblock experiments with the c-MET binding antibody onartuzumab analog showed that MCLA-129 competes for the same HGF-binding region of c-MET, which is distinct from the binding site of amivantamab according to Neijssen et al, 2021 (PMC8113745). MCLA-129 and amivantamab did not downmodulate EGFR or c-MET. ADCP was also comparable for MCLA-129 and amivantamab, as measured with monocyte-derived macrophages incubated with pHrodo-labeled target cells with readout of tumor cell phagocytosis on the Incucyte® system. In contrast, MCLA-129 displayed ADCC activity similar to or more potently than amivantamab in an ADCC reporter assay with either high affinity FcγRIII 158V-variant or low affinity 158F-variant effector cells in absence or presence of soluble EGFR and soluble c-MET. MCLA-129-induced ADCC appears to be less affected than amivantimab by the presence of soluble EGFR and soluble c-MET. In conclusion, MCLA-129 is a Biclonics® common light chain bispecific antibody with multiple MOA including inhibition of c-MET and EGFR ligand binding, ADCP and ADCC comparable or more potent than amivantamab. A phase 1/2 clinical trial of MCLA-129 in solid tumors is ongoing. These data support the further clinical development of MCLA-129 in patients with NSCLC and other solid tumors. Citation Format: David J.J. de Gorter, Alexandre Deshiere, Arjen Kramer, Martijn van Rosmalen, Franziska Mortensen, Cecile Geuijen. Preclinical evaluation of MCLA-129, a bispecific antibody targeting EGFR and c-MET on solid tumor cells, in comparison with amivantamab. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4999.
Abstract 5630: Robust spatial biomarker discovery through multi-platform multiplex image analysis of breast cancer clinical cohorts
Authors: Jennifer R. Eng, Elmar Bucher, Zhi Hu, Melinda Sanders, Bapsi Chakravarthy, Jennifer Pietenpol, Rosalie C. Sears, Summer Gibbs, Joe W. Gray, Koei Chin
Journal: Cancer Research (2023)

Abstract Spatial profiling of tissues promises to elucidate tumor-microenvironment interactions and enable development of spatial biomarkers to predict response to immunotherapy and other therapeutics. However, spatial biomarker discovery is often limited to small patient cohorts and single technologies, limiting statistical power and increasing the likelihood of technical artifacts. We utilized cyclic immunofluorescence, (CyCIF), to profile patient tissues from 102 breast cancer patients, 63 with clinical follow up. We then developed methods for comparative analysis of data from three disparate imaging technologies including our CyCIF images, as well as publicly available imaging mass cytometry and multiplex ion-beam imaging breast cancer data sets. We demonstrate similar single-cell phenotyping results across breast cancer patient cohorts imaged with the three methods, and furthermore, show agreement in the prognostic value of cellular and spatial biomarkers across platforms. We identified T cell infiltration as independently associated with longer survival in high-proliferation breast cancer, which was enriched for activated and spatially clustered T cells. A comparison of six spatial analysis methods revealed robust spatial biomarkers, including tumor-macrophage and tumor-fibroblast proximity associated with poor prognosis in estrogen receptor positive and triple negative tumors, respectively. Our methods enable assembly of larger clinical cohorts from diverse platforms to aid in predictive and prognostic spatial biomarker identification and validation. Citation Format: Jennifer R. Eng, Elmar Bucher, Zhi Hu, Melinda Sanders, Bapsi Chakravarthy, Jennifer Pietenpol, Rosalie C. Sears, Summer Gibbs, Joe W. Gray, Koei Chin. Robust spatial biomarker discovery through multi-platform multiplex image analysis of breast cancer clinical cohorts. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5630.
Abstract 6214: FANCA promotes transcription-coupled homologous recombination by catalyzing R-loops formation
Authors: Fang Li
Journal: Cancer Research (2023)

Abstract R loops arise from hybridization of RNA transcripts with template DNA during transcription, which are not only cause DNA damage in certain contexts as cancer hallmarks but also be important regulators of cellular processes. Recent findings revealed that DNA double-strand breaks (DSBs) elicit RNA-DNA hybrid formation. The RNA moiety of the R-loop displays an extraordinary potential to regulate multiple steps of homologous recombination (HR) by substituting for the double-stranded DNA (dsDNA) substrate on which DSB repair processes naturally occur. Here, we use the Damage At RNA Transcription assay to reveal colocalization of FANCA with R-loops in a highly transcribed genomic locus upon DNA damage. We further demonstrate FANCA participates in forming R-loops in the initial DSBs repair stage and assists in removing R-loops later. Besides, we find that highly purified human FANCA anneals synthetic single-stranded RNA (ssRNA) and ssDNA species to R-loops and binds R-loop substrates with high affinity, preferring guanine-rich sequences in vitro. Importantly, we illustrate that FANCA promotes HR efficiency via catalyzation of DNA: RNA hybrids at DSBs sites. Finally, a series of RNA and R-loop substrates are found to stimulate ID2 monoubiquitination, with activity corresponding to remove transient R- loops in later HR stage. In summary, our results support a mechanism whereby FANCA promotes the formation of temporary R-loops by annealing ssRNA and ssDNA species at DSBs in transcribed regions, thereby stimulating HR. Citation Format: Fang Li. FANCA promotes transcription-coupled homologous recombination by catalyzing R-loops formation. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6214.